rs372395294
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_001099404.2(SCN5A):c.1247A>G(p.Tyr416Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1247A>G | p.Tyr416Cys | missense_variant | 10/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1247A>G | p.Tyr416Cys | missense_variant | 10/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1247A>G | p.Tyr416Cys | missense_variant | 10/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1247A>G | p.Tyr416Cys | missense_variant | 10/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249238Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135206
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Familial isolated arrhythmogenic right ventricular dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2017 | The Y416C variant of uncertain significance has been identified in the SCN5A gene. The Y416C variant has previously been published in association with Brugada syndrome in a 62 year old male with ventricular fibrillation induced by electrical stimulation and a family history of sudden death (Nagase et al., 2008); however, segregation data was not provided. The Y416C variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y416C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (V411M, A413T, A413E) have been reported in the Human Gene Mutation Database in association with Long QT syndrome (LQTS) (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the Y416C variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 09, 2022 | This missense variant replaces tyrosine with cysteine at codon 416 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 28069705). This variant has been identified in 1/249238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at